Montserrat Butjosa

Large vessel involvement in biopsy-proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography

Background Necroscopic and surgical studies have suggested that giant cell arteritis (GCA) may target the aorta and its main branches. Imaging techniques are able to detect large vessel vasculitis (LVV) non-invasively in patients, but the prevalence of LVV in GCA has not been clearly established. Objective To assess prospectively the prevalence, characteristics and topography of LVV in patients with newly diagnosed GCA and to determine the associated clinical and laboratory features. Methods CT angiography (CTA) was performed in 40 consecutive patients with newly diagnosed biopsy-proven GCA. Patients were treatment-naïve or had been treated with corticosteroids for <3 days. Vessel wall thickness and vessel diameter (dilation or stenoses) at four aortic segments (ascending aorta, aortic arch, descending thoracic and abdominal aorta) and at the main aortic branches were evaluated. Results LVV was detected in 27 patients (67.5%). The vessels involved were as follows: aorta (26 patients, 65%), brachiocephalic trunk (19 patients, 47.5%), carotid arteries (14 patients, 35%), subclavian arteries (17 patients, 42.5%), axillary arteries (7 patients, 17.5%), splanchnic arteries (9 patients, 22.5%), renal arteries (3 patients, 7.5%), iliac arteries (6 patients, 15%) and femoral arteries (11 patients, 30%). Dilation of the thoracic aorta was already present in 6 patients (15%). Cranial ischaemic events were significantly less frequent in patients with LVV (p=0.029). Treatment-naïve patients had a higher frequency of LVV (77% vs 29%, p=0.005). Conclusions CTA-defined LVV occurs in two-thirds of patients with GCA at the time of diagnosis and aortic dilation is already present in 15%. Previous corticosteroid treatment may decrease CTA-detected LVV.

Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor α and interleukin‐6) in the long‐term followup of patients with giant cell arteritis

To assess the clinical relevance of increased circulating cytokines in patients with giant cell arteritis (GCA) after long‐term followup.

Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for aortic structural damage (aneurysm or dilatation)

Background Aortic structural damage (ASD) may complicate the course of patients with giant cell arteritis (GCA). However the frequency and outcome of ASD has not been assessed in long term prospective studies. Methods In a previous screening of 54 biopsy proven GCA patients, significant ASD was detected in 12 (22.2%) after a median follow-up of 5.4 years. These patients were periodically evaluated (every 4 years) over a median of 10.3 years (range 4–16.6 years) in order to investigate the development of new ASD and the outcome of previously detected abnormalities. Results 18 of the 54 patients abandoned the study due to death or other reasons. The remaining 36 patients were subjected to a second screening and 14 to a third screening. 12 (33.3%) of the 36 patients re-screened and 16 (29.6%) of the initial cohort developed ASD, all but one in the thoracic aorta. Aortic diameters at the ascending and descending aorta significantly increased over time. One patient (1.9% of the initial cohort) died from aortic dissection. Surgery was advised in eight (50%) patients with ASD but could only be performed in three patients (37.7%). The development of ASD was not associated with persistence of detectable disease activity. Conclusions The incidence of ASD is maximal within the first 5 years after diagnosis but continues developing over time, affecting up to 33.3% of individuals after long term follow-up. Once ASD occurs, dilatation increases over time, underlining the need for periodic evaluation. Surgical repair is feasible in about one-third of candidates.

Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients.

AbstractGiant cell arteritis (GCA) is a relapsing disease. However, the nature, chronology, therapeutic impact, and clinical consequences of relapses have been scarcely addressed. We conducted the present study to investigate the prevalence, timing, and characteristics of relapses in patients with GCA and to analyze whether a relapsing course is associated with disease-related complications, increased glucocorticoid (GC) doses, and GC-related adverse effects. The study cohort included 106 patients, longitudinally followed by the authors for 7.8 ± 3.3 years. Relapses were defined as reappearance of disease-related symptoms requiring treatment adjustment. Relapses were classified into 4 categories: polymyalgia rheumatica (PMR), cranial symptoms (including ischemic complications), systemic disease, or symptomatic large vessel involvement. Cumulated GC dose during the first year of treatment, time required to achieve a maintenance prednisone dose <10 mg/d (T10), <5 mg/d (T5), or complete prednisone discontinuation (T0), and GC-related side effects were recorded. Sixty-eight patients (64%) experienced at least 1 relapse, and 38 (36%) experienced 2 or more. First relapse consisted of PMR in 51%, cranial symptoms in 31%, and systemic complaints in 18%. Relapses appeared predominantly, but not exclusively, within the first 2 years of treatment, and only 1 patient developed visual loss. T10, T5, and T0 were significantly longer in patients with relapses than in patients without relapse (median, 40 vs 27 wk, p  < 0.0001; 163 vs 89.5 wk, p = 0.004; and 340 vs 190 wk, p = 0.001, respectively). Cumulated prednisone dose during the first year was significantly higher in relapsing patients (6.2 ± 1.7 g vs 5.4 ± 0.78 g, p = 0.015). Osteoporosis was more common in patients with relapses compared to those without (65% vs 32%, p = 0.001). In conclusion, the results of the present study provide evidence that a relapsing course is associated with higher and prolonged GC requirements and a higher frequency of osteoporosis in GCA.

Central nervous system vasculitis: still more questions than answers.

The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels. These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNS vasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situations are severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focal symptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficult because, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography has limited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosing blood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However, since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement by systemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressive treatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recommended for patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemic vasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cell arteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis, where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions of intracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role.

The spectrum of vascular involvement in giant‐cell arteritis: clinical consequences of detrimental vascular remodelling at different sites

Although repeatedly reported in the literature, the extracranial involvement by giant‐cell arteritis has been considered anecdotal until recent years. The emergence of new or improved imaging techniques along with a closer follow‐up of these patients and their increase in life expectancy are beginning to underline that the clinical impact of extracranial involvement by GCA may be more relevant than previously thought. This review focuses on the extent of vascular involvement in GCA as reported by pathology and imaging studies as well as the clinical consequences of imperfect vascular remodelling in various vascular territories.

Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis

Background Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment. Methods Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay. Results Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro-inflammatory cytokines (particularly IL-1β and IFNγ), chemokines (CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES) and MMP-9 as well as IL-1β and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1β, IL-6, TNFα, IFNγ, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III). Conclusions Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents.

Treatment with angiotensin II receptor blockers is associated with prolonged relapse-free survival, lower relapse rate, and corticosteroid-sparing effect in patients with giant cell arteritis

OBJECTIVE To determine whether concomitant treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) is associated with changes in the outcome of patients with giant cell arteritis (GCA). METHODS A study cohort of 106 patients with biopsy-proven GCA was longitudinally followed up for 7.8 ± 3.3 years. Patients were stratified according to their treatment with ACEI, ARB, or no ACEI/ARB. Time to first relapse, number of flares, time to achieve a stable prednisone dose <10mg/day and <5mg/day with no relapses, time required to completely discontinue prednisone, cumulative dose of prednisone received during the first year, and concentrations of acute-phase reactants at pre-defined time points (baseline, 6, 12, 18, and 24 months) were compared among the 3 groups. Cox proportional hazards models were performed to adjust for potential confounders. RESULTS Patients receiving ARB presented a significantly longer relapse-free survival than patients treated with ACEI or patients not receiving ACEI/ARB (p = 0.02). The adjusted hazard ratio for relapses in patients treated with ARB was 0.32 (95% CI: 0.12-0.81, p = 0.017). In addition, patients who received ARB achieved a prednisone maintenance dose <10mg/day faster than all other patients (p = 0.0002). No significant differences were observed among groups in acute-phase reactant levels during follow-up. However, patients not receiving ACEI/ARB had significantly higher C-reactive protein and haptoglobin concentrations than those receiving ACEI or ARB at various time points. CONCLUSIONS Addition of ARB to glucocorticoids is associated with lower relapse rate and more prolonged disease-free survival in patients with GCA.

OP0206 Diagnostic Performance of PET/CT in Patients with Newly Diagnosed, Biopsy-Proven, Giant-Cell Arteritis. a Prospective, Case-Control Study Using Roc Analysis at Different Vascular Territories

Background PET has emerged as a promising diagnostic tool for the detection of large-vessel involvement in giant cell arteritis (GCA). In a recent meta-analysis including some heterogeneous studies, PET sensitivity and specificity for GCA diagnosis were 0.8 and 0.89, respectively. However, the lack of a standardised definition of vasculitis based on FDG uptake is one of the most important limitations in the diagnostic performance of PET. Atherosclerosis and vascular ageing highly influence FDG uptake, and may lead to vasculitis misdiagnosis. Objectives To prospectively assess the utility of FDG-PET for GCA diagnosis in a cohort of newly diagnosed biopsy proven patients, using a ROC-analysis of FDG uptake at different vascular beds. Methods From November 2006 to March 2011, all patients diagnosed at our institution were assessed for their potential participation in the study. The inclusion criteria were 1) newly diagnosed, biopsy-proven GCA, 2) fulfilment of at least 3 ACR classification criteria for GCA and 3) signed informed consent. Exclusion criteria included 1) lack of consent to participate, 2) severe hyperglycemia at the moment of PET performance and 3) treatment with corticosteroids for more than 3 days. The control group included patients with no chronic inflammatory diseases, matched for gender, age and traditional cardiovascular risk factors, who underwent PET for staging of lung cancer at early stage (with no metastases or contact with vascular structures). The standardized uptake value (SUV) was calculated at four aortic segments (ascending thoracic aorta, aortic arch, descending thoracic aorta and abdominal aorta), as well as at the supraaortic vessels (subclavian, carotid and axillary arteries) and the iliofemoral territory. Receiver–operator characteristics curves were used to calculate sensitivity and specificity at each vascular territory. Results 30 patients and 20 controls were included. Mean SUV in each territory was significant higher in GCA patients than in controls. Mean SUV at supraaortic vessels showed the best area under curve (AUC) (0,826). According to this, a FDG uptake cut-off of 1,70 achieved a sensitivity and specificity of 81 and 79%, respectively, for GCA diagnosis (p<0,001). FDG uptake at the aorta showed a more limited utility (AUC = 0,740), with a sensitivity and specificity of 80 and 48, respectively, using a cut-off of 2,48 (p=0,001). Conclusions Using an objective and reproducible FDG uptake cut-off, PET shows a remarkable sensitivity and specificity for the diagnosis of GCA. Supraaortic branches seem to be the most suitable vascular field for this purpose. Supported by SAF 08/0438 and SAF 11/30073. Disclosure of Interest None Declared